Methemoglobinemia

Summary

Methemoglobinemia (MONDO:0001117) is a disease caused by CYB5R3 (GenCC Definitive), with 2 cohort genes and 8 clinical trials. Top therapeutic interventions include methylene blue cation and dapsone.

At a glance

• Causal gene: CYB5R3 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 1
• Clinical trials: 8

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	methemoglobinemia
Mondo ID	MONDO:0001117
MeSH	D008708
DOID	DOID:10783
ICD-10-CM	D74
NCIT	C34817
SNOMED CT	38959009
UMLS	C0025637
MedGen	6339
GARD	0022885
MedDRA	10027496
Is cancer (heuristic)	no

Also known as: methemoglobinemias

Data availability: 1 ClinVar variant · 1 GenCC gene-disease record.

Disease family

An umbrella term covering 2 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › hematologic disorder › erythrocyte disorder › hemoglobinopathy › methemoglobinemia

Related subtypes (3): sulfhemoglobinemia, inherited hemoglobinopathy, acquired hemoglobinopathy

Subtypes (2): drug-induced methemoglobinemia, hereditary methemoglobinemia

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

1 retrieved; paginated sample, class counts are floors:

1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
523258	GRCh37/hg19 17p11.2(chr17:16936603-18184130)	ALKBH5	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 1 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
CYB5R3	Definitive	Autosomal recessive	methemoglobinemia	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CYB5R3	Orphanet:621	Autosomal recessive methemoglobinemia

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
CYB5R3	HGNC:2873	ENSG00000100243	P00387	NADH-cytochrome b5 reductase 3	gencc
ALKBH5	HGNC:25996	ENSG00000091542	Q6P6C2	RNA demethylase ALKBH5	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CYB5R3	NADH-cytochrome b5 reductase 3	Catalyzes the reduction of two molecules of cytochrome b5 using NADH as the electron donor.
ALKBH5	RNA demethylase ALKBH5	Dioxygenase that specifically demethylates N(6)-methyladenosine (m6A) RNA, the most prevalent internal modification of messenger RNA (mRNA) in higher eukaryotes.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Enzyme (other)	2	12.0×	0.007

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CYB5R3	Enzyme (other)	yes	1.6.2.2	OxRdtase_FAD/NAD-bd, Flavoprot_Pyr_Nucl_cyt_Rdtase, CBR-like
ALKBH5	Enzyme (other)	yes	1.14.11.53	AlkB-like, ALKBH5, AlkB-like_sf

Expression context

Cohort genes with no expression data: 0.

2 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
descending thoracic aorta	1
right coronary artery	1
thoracic aorta	1
cardiac muscle of right atrium	1
left ventricle myocardium	1
tibialis anterior	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CYB5R3	294	ubiquitous	marker	right coronary artery, descending thoracic aorta, thoracic aorta
ALKBH5	252	ubiquitous	marker	tibialis anterior, left ventricle myocardium, cardiac muscle of right atrium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CYB5R3	2,715
ALKBH5	1,387

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ALKBH5	Q6P6C2	11
CYB5R3	P00387	5

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 12. Enrichment computed across 2 evidence-associated genes (2 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
DNA Damage Reversal	1	815.7×	0.006	ALKBH5
Reversal of alkylation damage by DNA dioxygenases	1	815.7×	0.006	ALKBH5
Vitamin C (ascorbate) metabolism	1	713.8×	0.006	CYB5R3
Phase I - Functionalization of compounds	1	109.8×	0.026	CYB5R3
Metabolism of water-soluble vitamins and cofactors	1	90.6×	0.026	CYB5R3
Biological oxidations	1	64.9×	0.029	CYB5R3
Metabolism of vitamins and cofactors	1	58.3×	0.029	CYB5R3
DNA Repair	1	49.2×	0.030	ALKBH5
Innate Immune System	1	12.8×	0.102	CYB5R3
Neutrophil degranulation	1	11.5×	0.102	CYB5R3
Immune System	1	6.5×	0.162	CYB5R3
Metabolism	1	5.8×	0.165	CYB5R3

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
gamma-delta T cell proliferation	1	8426.0×	0.002	ALKBH5
regulation of mRNA export from nucleus	1	1053.2×	0.006	ALKBH5
membraneless organelle assembly	1	561.7×	0.006	ALKBH5
regulation of mRNA processing	1	443.5×	0.006	ALKBH5
nitric oxide biosynthetic process	1	351.1×	0.006	CYB5R3
mRNA destabilization	1	337.0×	0.006	ALKBH5
blood circulation	1	255.3×	0.007	CYB5R3
cholesterol biosynthetic process	1	210.7×	0.008	CYB5R3
regulation of translation	1	109.4×	0.013	ALKBH5
response to hypoxia	1	47.9×	0.027	ALKBH5
mRNA processing	1	39.4×	0.030	ALKBH5
spermatogenesis	1	17.6×	0.061	ALKBH5
cell differentiation	1	14.6×	0.068	ALKBH5

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 1

Druggability breadth: 2 of 2 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ALKBH5	3	3
CYB5R3	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
BISANTRENE	3	ALKBH5
SUCCINIC ACID	3	ALKBH5
BREQUINAR	2	ALKBH5

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
ALKBH5	130	Binding:130
CYB5R3	18	Binding:18

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
CYB5R3	1.6.2.2	cytochrome-b5 reductase
ALKBH5	1.14.11.53	mRNA N6-methyladenine demethylase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
ALKBH5	130

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

3 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
BISANTRENE	3	ALKBH5
SUCCINIC ACID	3	ALKBH5
BREQUINAR	2	ALKBH5

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	1	ALKBH5
C	Druggable family + PDB, no drug	1	CYB5R3
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
CYB5R3	18	—

Clinical trials & evidence

Clinical trials

Clinical trials: 8.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	6
PHASE1	2

Top trials by phase / activity

NCT	Phase	Status	Title
NCT02478281	PHASE1	COMPLETED	Safety, Tolerability, and Pharmacokinetic Study of Methylene Blue Following a 1 mg/kg Intravenous Dose in Healthy Adults
NCT02493283	PHASE1	COMPLETED	Pharmacokinetics and Distribution of Dapsone in Leucocytes After Single-dose and Multiple-dose Administration
NCT00993694	Not specified	COMPLETED	Methemoglobinemia in Young Patients With Hematologic Cancer or Aplastic Anemia Treated With Dapsone
NCT01402869	Not specified	COMPLETED	Methemoglobin Levels in Generally Anesthetized Pediatric Dental Patients Receiving Local Anesthetics
NCT01766999	Not specified	COMPLETED	Methemoglobinemia After Liposuction - Diagnostic by Pulse Oximetry and Blood Gas Analysis.
NCT03542760	Not specified	COMPLETED	Acquired Methemoglobinemia Observational Registry
NCT06309641	Not specified	COMPLETED	Methemoglobinemia Following Intravenous Iron Treatment
NCT06958822	Not specified	COMPLETED	Ferric Carboxymaltose Methemoglobinemia Study

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
METHYLENE BLUE CATION	4	6
DAPSONE	4	1